Role of gastrin-peptides in Barrett's and colorectal carcinogenesis

Table 1 Studies assessing expression levels and/or biological effects of gastrin through its interaction with cholecystokinin-B receptor

Ref.	Specimen	CCKBR expression	G17 expression	G17 effects
Haigh et al[4]	Esophageal biopsies from healthy, esophagitis, BE and EAC patients; Ex vivo culture of BE cells; OE33(E)GR cells	CCKBR is expressed in 3/9 of healthy, 5/7 esophagitis, 10/10 BE and 7/12 EAC samples	Not assessed	G17 stimulates cell proliferation through CCKBR
Konturek et al[46]	Tumor and plasma samples from CRC patients; Plasma and normal colonic mucosa biopsies from healthy subjects	All the tumor samples showed CCKBR expression	CRC patients showed normal G17 plasma levels, and higher progastrin levels than healthy subjects; Celecoxib diminished plasma gastrin and progastrin levels	Not assessed
Smith et al[49]	Healthy colonic mucosa and colonic polyps biopsies	Normal colonic mucosa didn’t show CCKBR expression; Most of the polyps analyzed showed CCKBR expression	Most of the polyps showed higher expression of the gastrin precursors than amidated forms	Not assessed
Harris et al[70]	Healthy esophagus and BE biopsies; OE19 and OE33 cell culture; OE21 cell culture	All three esophageal cancer cell lines express CCKBR; BE biopsies show higher CCKBR expression levels than normal esophageal biopsies	BE samples express higher gastrin levels than healthy esophageal biopsies	G17 increases activation of the antiapoptotic factor PKB/Akt, through CCKBR

BE: Barrett’s esophagus; EAC: Esophageal adenocarcinoma; CCKBR: Cholecystokinin-B receptor; G17: Amidated gastrin-17; CRC: Colorectal carcinoma; OE19 and OE33 cells: Esophageal adenocarcinoma cell lines; OE21 cells: Esophageal squamous carcinoma cell line; OE33(E)GR cells: Esophageal adenocarcinoma cells permanently transfected with the human CCKB receptor.

Table 2 Experimental studies in animal models exploring the impact of increased levels of gastrin peptides

Ref.	Animal model	Alteration on gastrin peptides levels	Hypergastrinemia effects
Cobb et al[2]	Fabp-wt mice; Fabp-mt mice	Fabp-wt mice express human PG in intestinal mucosa and Fabp-mt mice express a mutated form of human PG; Both mice show PG expression at similar levels as seen in hypergastrinemia	Mice overexpressing human PG (either the wild-type and the mutated form) are more likely to develop colonic tumors in response to AOM
Wang et al[5]	INS-GAS mice; hGAS mice	INS-GAS mice overexpress human amidated gastrin in the pancreatic islands; hGAS mice overexpress human PG in the liver	Both forms of gastrin showed similar proliferative effects on normal colonic mucosa
Havu et al[34]	Sprague-Dawley rats treated with ranitidine (2g/kg per day)	Rats showed a 3-fold increase in plasma gastrin levels	19/100 rats developed ECL carcinoids while no carcinoma was found in control animals
Watson et al[43]	APCMin+/- mice (model of multiple intestinal neoplasia) treated with omeprazole (75 mg/kg in a single oral dose)	Omeprazole increased only amidated gastrin plasma levels	PPI-induced hypergastrinemia reduced mice survival; Hypergastrinemia increased colonic adenomas proliferation; Hypergastrinemia did not increase the incidence of intestinal tumors
Ferrand et al[90]	MTI/G-Gly mice; hGAS mice	MTI/G-Gly mice overexpress human G-Gly throughout the gastrointestinal tract; hGAS mice overexpress human PG in the liver	Both G-Gly and PG strongly up-regulate Src, JAK2 and STAT3 activation; PG produced significantly great ERK and Akt pathways activation and TGF-α overexpression
Koh et al[95]	MTI/G-Gly mice	MTI/G-Gly mice overexpress human G-Gly throughout the gastrointestinal tract	Goblet cells hyperplasia and colonic hyperproliferation; Hypergastrinemia did not increase the incidence of GI tumors, but 3/10 mice developed bronchoalveolar carcinoma
Ottewell et al[98]	G-/-hg+/+ mice; G-/-hg-/- mice	G-/-hg+/+ mice express human PG and no murine gastrin; G-/-hg-/- mice do not express any forms of gastrin	PG increased colonic proliferation; PG exerts mitotic effects on colonic epithelia but does not seem to affect the small intestine epithelia

PG: Progastrin; AOM: Azoxymethane; ECL: Enterochromaffin-like cells; PPI: Proton pump inhibitors; G-Gly: Glycine-extended gastrins; JAK2: Janus-activated kinase 2; STAT3: Signal transducer and activator of transcription 3; ERK: Extracellular-signal regulated kinase; Akt: Protein kinase B; TGF-α: Transforming growth factor-alpha; GI: Gastrointestinal.

Table 3 Clinico-epidemiologic studies exploring the effects of proton pump inhibitors use in human beings

Ref.	Population studied	Treatment, dose and duration	Effects on gastrin levels	Physiopathological effects
Brunner et al[35]	143 patients with duodenal or stomach ulcer and GERD	Omeprazole 40 mg/d 1-5 yr	Plasma gastrin levels increased 4-fold after 4 mo of therapy	Hyperplasia of argyrophil cells from oxyntic mucosa; No increase in dysplasia or neoplasia rates was observed
Klinkenberg-Knol et al[37]	91 GERD patients	Omeprazole 20-40 mg/d 5 yr	Median serum gastrin levels increased from 60 to 162 ng/L and reached a plateau during maintenance treatment	Esophagitis symptoms ameliorated; Gastric hyperplasia rates increased from 2.5% at the beginning of the study to 20% at last biopsy
Nemeth et al[39]	10 patients with oesophagitis	Omeprazole 20 mg/d 6-8 wk	Plasma levels of amidated gastrins increased from 18 to 48 pmol/L; Antral levels of progastrin increased 6-fold while amidated gastrins and G-Gly remain unaltered	Not assessed
Wang et al[42]	82 BE patients; 13 GERD patients	All patients were on PPI therapy, once or twice daily during a median time of 74 mo	The median serum gastrin levels (40 pmol/L) was not related to the degree of dysplasia in BE	Higher serum gastrin levels were associated with high grade dysplasia and adenocarcinoma
Creutzfeldt et al[53]	74 patients with esophagitis or peptic ulcer	Omeprazole 40 mg/d 1-5 yr	Plasma gastrin levels increased 4-fold in 23% of patients	Patients with higher serum gastrin levels developed hyperplasia of the gastric argyrophil cells; This hyperplasia may not necessary be related to high gastrin levels
Kuipers et al[54]	177 GERD patients	105 patients treated with omeprazole 20-40 mg/d 5 yr; 72 patients treated with fundoplication	Not assessed	Patients treated with omeprazole and infected with H.pylori infection are at increased risk of atrophic gastritis
Lamberts et al[55]	74 peptic ulcer patients	Omeprazole 48 mo	Median gastrin levels moderately increased after 3 mo of therapy and reached a plateau during maintenance treatment	Significant argyrophil cell hyperplasia

GERD: Gastroesophageal reflux disease; G-Gly: Glycine-extended gastrins; BE: Barrett’s esophagus; PPI: Proton pump inhibitors.